CN102399212A - Dexlansoprazole crystal form and preparation method thereof - Google Patents
Dexlansoprazole crystal form and preparation method thereof Download PDFInfo
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- CN102399212A CN102399212A CN2011102430316A CN201110243031A CN102399212A CN 102399212 A CN102399212 A CN 102399212A CN 2011102430316 A CN2011102430316 A CN 2011102430316A CN 201110243031 A CN201110243031 A CN 201110243031A CN 102399212 A CN102399212 A CN 102399212A
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Abstract
The present invention relates to a dexlansoprazole crystal form and a preparation method thereof. The d values of characteristic peaks of the dexlansoprazole crystal form in an x-ray powder diffraction pattern are 12.234, 5.640, 5.401, 5.087, 4.990, 4.839, 4.605, 4.354, 3.959 and 3.648.
Description
Technical field
The present invention relates to new crystal of a kind of R-lansoprazole and preparation method thereof, the d value of its X-ray powder diffraction pattern characteristic peak is 12.234,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648.
Background technology
CN1150186C discloses two kinds of crystal formations that are suitable for the R-lansoprazole of pharmacy.Wherein the X-ray powder diffraction analysis of A crystal formation locates to have characteristic peak in following spacing (d): 11.68,6.77,5.84,5.73,4.43,4.09,3.94,3.89, and 3.69,3.41 and 3.11 dusts; The X-ray powder diffraction analysis of B crystal formation locates to have characteristic peak in following spacing (d): 13.22,9.60,8.87,8.05,6.61,5.91,5.64,5.02, and 4.48,3.50 and 2.29 dusts.
Summary of the invention
The object of the present invention is to provide a kind of R-lansoprazole new crystal, the d value of its X-ray powder diffraction pattern characteristic peak is 12.234,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648; Preferably, the d value is 12.234,9.563,8.838,8.022,7.261,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648; More preferably, its X-ray powder diffraction pattern is shown in accompanying drawing 1.
Another purpose of the present invention is to provide a kind of method for preparing said new crystal; This method is dissolved in R-lansoprazole or its crystal formation that crystallization gets said crystal formation in the organic solvent; Wherein said organic solvent particular methanol more preferably contains the methyl alcohol of ammoniacal liquor, more preferably contains the ammoniacal liquor of 25% concentration.
Through the X-ray diffraction analysis, the crystal formation of R-lansoprazole provided by the present invention is different from A crystal formation and B crystal formation, and its stable preparation process is controlled, favorable reproducibility; Solvability is suitable with the B crystal formation with the A crystal formation in conventional solvent such as methyl alcohol, second alcohol and water, draws moist quite with the B crystal formation, and stable crystal form property is good, is suitable for pharmacy.
Description of drawings
Fig. 1 makes the X-ray powder diffraction figure of R-lansoprazole crystal formation for embodiment one.
Embodiment
The preparation of embodiment one R-lansoprazole crystal formation
1,2-acetoxy-methyl-4-chloro-3-picoline is synthetic
With raw material 4-chloro-2,3 dimethyl pyridine-N-oxide compound, 1083.7g, 6.88mol are dissolved in the toluene (7000m1), are heated to 90 ℃, and (2053.2g, 20.11mol), temperature is controlled at 90-110 ℃ slowly to drip diacetyl oxide.Finish, be incubated 105-110 ℃ of reaction 1.5h, the TLC detection reaction finishes.Cold slightly, 60 ℃ remove solvent under reduced pressure, 2-acetoxy-methyl-4-chloro-3-picoline (yellow oil, 1627.2g).
2,2-methylol-4-chloro-3-picoline is synthetic
Step 1 is made 2-acetoxy-methyl-4-chloro-3-picoline be dissolved in methyl alcohol (1450ml); Be cooled to 0-5 ℃; Drip the solution of Pottasium Hydroxide (1597.0g) and water (7000ml), the control reacting liquid temperature is below 10 ℃, and about 30min drips off; Continue insulation reaction 20min, the TLC detection reaction finishes.Pressure reducing and steaming methyl alcohol with methylene dichloride (2300ml * 3) extraction, merges organic phase, uses the 1000.0g anhydrous sodium sulfate drying.Filter, filtrate decompression concentrate 2-methylol-4-chloro-3-picoline (yellow oil, 913.1g).
3,2-chloromethyl-4-chloro-3-picoline is synthetic
Step 2 is made 2-methylol-4-chloro-3-picoline be dissolved in trichloromethane (4000ml), be cooled to 0～-5 ℃, stir dripping thionyl chloride (590.3g down; 4.96mol), control reaction temperature is below 10 ℃, and about 40min drips off; Continue insulation reaction 20min, the TLC detection reaction finishes.Concentrating under reduced pressure gets brown solid, slowly adds frozen water (3L), transfers pH to 8-9 with saturated sodium bicarbonate (3000ml) solution; Extract with methylene dichloride (1700ml * 3); Merge organic phase, with saturated nacl aqueous solution (3L) washing once, promptly get the solution of 2-chloromethyl-4-chloro-3-picoline.
4,2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfenyl)-1H-benzoglyoxaline is synthetic
With sodium hydroxide (487.6g, 12.19mol) water-soluble (4800ml) is cooled to 10～15 ℃; Add 2-mercaptobenzimidazole (487.6g; 3.25mol) and triethyl benzyl ammonia chloride (146.6g, 0.63mol), stirring 15min; Drip the solution of 2-chloromethyl-4-chloro-3-picoline that step 3 makes then, temperature control is below 15 ℃.Finish, in 25～30 ℃ of following stir about 2h, TLC detects 2-chloromethyl-4-chloro-3-picoline and reacts completely; Reaction solution is concentrated into about 6000ml, is cooled to 0 ℃ and stirs 1h, filters; Solid is with methylene dichloride (1150ml) washing, and water (1200ml * 3) washs, 40 ℃ of vacuum-drying 8h; 2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfenyl)-1H-benzoglyoxaline (the off-white color solid, 645.1g).
5, R-2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline is synthetic
2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfenyl)-1H-benzoglyoxaline (645.1g), toluene (3600ml) and L-(+) diethyl tartrate (168ml) that step 4 is made mix; Be heated to 50-60 ℃ of reaction 0.5h; Add tetraisopropoxy titanium (131ml), continue under this temperature, to react 1h.Reaction solution is cooled to 20 ℃, adds diisopropylethylamine (135ml), be cooled to-10 ℃, temperature control-10 ℃ adds 80% cumene hydroperoxide (1203ml) to 0 ℃, and controlled temperature is at-5 ℃ to 0 ℃ reaction 4h.TLC analyzes primitive reaction and finishes; The hypo solution (1600ml) of adding 30% stirs 10min, drips normal hexane (1550ml), t-butyl methyl ether (1550ml), normal hexane (13000ml) successively in 0 ℃ to 10 ℃; Separate out white solid; Filter, (4: 1,1250ml) washing was 1 time with t-butyl methyl ether-toluene.This solid is dissolved in the acetone (15L), filters, in filtrating, drip water (40L); Separate out solid; Filter, 50 ℃ of vacuum-drying 6h get R-2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline (322.2g; The HPLC normalization method detects: 99.6%, the S isomer does not detect).
6, the R-lansoprazole bullion is synthetic
In reaction flask, add R-2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline (322.2g), methyl-sulphoxide (2100ml), trifluoroethanol (727.8g), sodium hydroxide (235.6g) that step 5 makes successively; Be warmed up to 60～70 ℃; React about 4h, TLC analyzes primitive reaction and finishes.With the reaction solution cool to room temperature, drip water (20L), transfer about pH to 7 with glacial acetic acid, separate out solid, stir 5min, filter, get the off-white color solid.This solid is dissolved in ETHYLE ACETATE (5L), anhydrous magnesium sulfate (1000.0g) drying.Filter, filtrate decompression concentrate brown oil.With silica gel short column column chromatography, eluent is ETHYLE ACETATE-normal hexane-methyl alcohol (10: 10: 1), collects qualified component with this oily matter, concentrates, and gets spumescence solid (235.6g).With this solid at room temperature be dissolved in ammoniacal liquor (12.5%, 5040ml) in, filter, filtrating is with methylene dichloride (1000ml * 3) washing, water layer with glacial acetic acid accent pH to 9 about, separate out white solid.Stir 5min, filter, solid is with frozen water (1000ml) washing, dry 24h, must the R-lansoprazole bullion (the off-white color solid, 150.0g).
7, the preparation of R-lansoprazole crystal formation
With R-lansoprazole bullion (150.0g), be dissolved in 95% methyl alcohol (600ml), add 25% ammoniacal liquor (37.5ml); In stirring at room 30min, filter, will filtrate concentrates; A large amount of off-white color solids are separated out in cooling, filtration, the dry R-lansoprazole crystal formation 105.0g that gets.
1HNMR(CDCl
3，400M)δ：4.784-4.904(d-d，2H，CF
3 CH 2 O)，2.233(s，3H，-CH3)。
Through accompanying drawing 1 conclusive evidence, this product is the R-lansoprazole new crystal.
Test Example one each crystal formation solvability and draw moist simultaneous test
Conclusion (of pressure testing): crystal formation provided by the present invention solvability and A crystal formation, B crystal formation in conventional solvents such as methyl alcohol, ethanol, water is suitable; Draw moist aspect, suitable with the B crystal formation, all have draw moist.
Test Example two embodiment one make the stability test accelerated test (25 ℃ of RH60%) of crystal formation
Test of long duration (2-8 ℃)
Test of long duration (20 ℃)
From the stability test result, the stable crystal form property that the present invention obtained is effective, is fit to pharmaceutical applications.
Claims (7)
1. R-lansoprazole crystal formation, the d value of its X-ray powder diffraction pattern characteristic peak is 12.234,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648.
2. R-lansoprazole crystal formation according to claim 1, the d value of its X-ray powder diffraction pattern characteristic peak is 12.234,9.563,8.838,8.022,7.261,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648.
3. R-lansoprazole crystal formation according to claim 2, its X-ray powder diffraction pattern is shown in accompanying drawing 1.
4. method for preparing like any said R-lansoprazole crystal formation of claim 1～3 wherein is dissolved in R-lansoprazole or its crystal formation that crystallization gets said crystal formation in the organic solvent.
5. the method for preparing the R-lansoprazole crystal formation according to claim 4, wherein said organic solvent are methyl alcohol.
6. the method for preparing the R-lansoprazole crystal formation according to claim 5 wherein adds ammoniacal liquor in the methyl alcohol.
7. the method for preparing the R-lansoprazole crystal formation according to claim 6, wherein said ammonia concn are 25%.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234265A (en) * | 2011-08-08 | 2011-11-09 | 天津市汉康医药生物技术有限公司 | Lansoprazole compound |
| CN103664889A (en) * | 2013-12-19 | 2014-03-26 | 悦康药业集团有限公司 | Lansoprazole compound |
| CN103772359A (en) * | 2014-01-27 | 2014-05-07 | 马魁 | Lansoprazole compound |
| CN104086532A (en) * | 2014-07-21 | 2014-10-08 | 上海右手医药科技开发有限公司 | Dexlansoprazole polycrystalline type generated by alkylamine inducing as well as preparation method and pharmaceutical composition thereof |
| CN104958276A (en) * | 2015-07-30 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical lansoprazole composition capsule for treating gastric ulcer |
| CN104997738A (en) * | 2015-08-10 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine lansoprazole compound dry suspension treating gastropathy |
| CN105017218A (en) * | 2015-07-01 | 2015-11-04 | 合肥安德生制药有限公司 | R-lansoprazole crystal form and preparation method therefor |
| CN106749182A (en) * | 2016-11-08 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal-form compound and preparation method thereof |
| CN108084158A (en) * | 2016-11-23 | 2018-05-29 | 江苏豪森药业集团有限公司 | The preparation method of R-lansoprazole |
| CN108164507A (en) * | 2016-12-07 | 2018-06-15 | 天津药物研究院有限公司 | A kind of R-lansoprazole monocrystalline and its preparation method and application |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1306375A1 (en) * | 2000-08-04 | 2003-05-02 | Takeda Chemical Industries, Ltd. | Salts of benzimidazole compound and use thereof |
| CN1426406A (en) * | 2000-04-28 | 2003-06-25 | 武田药品工业株式会社 | Process for producing optically active sulfoxide devivative' |
| EP1334971A1 (en) * | 2000-10-12 | 2003-08-13 | Takeda Chemical Industries, Ltd. | Benzimidazole compounds, process for producing the same and use thereof |
| EP1437352A1 (en) * | 2001-09-25 | 2004-07-14 | Takeda Chemical Industries, Ltd. | Benzimidazole compound, process for producing the same, and use thereof |
| WO2009117489A1 (en) * | 2008-03-18 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
| CN102108077A (en) * | 2009-12-23 | 2011-06-29 | 江苏豪森医药集团有限公司 | Method for preparing dexlansoprazole |
-
2011
- 2011-08-19 CN CN201110243031.6A patent/CN102399212B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1426406A (en) * | 2000-04-28 | 2003-06-25 | 武田药品工业株式会社 | Process for producing optically active sulfoxide devivative' |
| EP1306375A1 (en) * | 2000-08-04 | 2003-05-02 | Takeda Chemical Industries, Ltd. | Salts of benzimidazole compound and use thereof |
| EP1334971A1 (en) * | 2000-10-12 | 2003-08-13 | Takeda Chemical Industries, Ltd. | Benzimidazole compounds, process for producing the same and use thereof |
| EP1437352A1 (en) * | 2001-09-25 | 2004-07-14 | Takeda Chemical Industries, Ltd. | Benzimidazole compound, process for producing the same, and use thereof |
| WO2009117489A1 (en) * | 2008-03-18 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
| CN102108077A (en) * | 2009-12-23 | 2011-06-29 | 江苏豪森医药集团有限公司 | Method for preparing dexlansoprazole |
Non-Patent Citations (1)
| Title |
|---|
| 杜有国等: "R-(+)-兰索拉唑的合成研究", 《化工时刊》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234265A (en) * | 2011-08-08 | 2011-11-09 | 天津市汉康医药生物技术有限公司 | Lansoprazole compound |
| CN103664889A (en) * | 2013-12-19 | 2014-03-26 | 悦康药业集团有限公司 | Lansoprazole compound |
| CN103664889B (en) * | 2013-12-19 | 2014-11-19 | 悦康药业集团有限公司 | Lansoprazole compound |
| CN103772359A (en) * | 2014-01-27 | 2014-05-07 | 马魁 | Lansoprazole compound |
| CN104086532A (en) * | 2014-07-21 | 2014-10-08 | 上海右手医药科技开发有限公司 | Dexlansoprazole polycrystalline type generated by alkylamine inducing as well as preparation method and pharmaceutical composition thereof |
| CN105017218A (en) * | 2015-07-01 | 2015-11-04 | 合肥安德生制药有限公司 | R-lansoprazole crystal form and preparation method therefor |
| CN104958276A (en) * | 2015-07-30 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical lansoprazole composition capsule for treating gastric ulcer |
| CN104997738A (en) * | 2015-08-10 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine lansoprazole compound dry suspension treating gastropathy |
| CN106749182A (en) * | 2016-11-08 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal-form compound and preparation method thereof |
| CN108084158A (en) * | 2016-11-23 | 2018-05-29 | 江苏豪森药业集团有限公司 | The preparation method of R-lansoprazole |
| CN108164507A (en) * | 2016-12-07 | 2018-06-15 | 天津药物研究院有限公司 | A kind of R-lansoprazole monocrystalline and its preparation method and application |
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